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Pharmacology: Pharmacodynamics: Dexmedetomidine is a selective alpha-2 receptor agonist with a broad range of pharmacological properties. It has a sympatholytic effect through the decrease of the release of noradrenaline in sympathetic nerve endings. The sedative effects are mediated through the decreased firing of locus coeruleus, the predominant noradrenergic nucleus, situated in the brainstem. Dexmedetomidine has analgesic and anaesthetic/ analgesic-sparing effects. The cardiovascular effects depend on the dose; with lower infusion rates the central effects dominate leading to decrease in heart rate and blood pressure. With higher doses, peripheral vasoconstriction effects prevail leading to an increase in systemic vascular resistance and blood pressure, while the bradycardic effect is further emphasised. Dexmedetomidine is relatively free from respiratory depressive effects when given as monotherapy to healthy subjects.
Dexmedetomidine was similar to midazolam and propofol on the time in target sedation range in a predominantly medical population requiring prolonged light to moderate sedation (RASS 0 to -3) in the ICU for up to 14 days, reduced the duration of mechanical ventilation compared to midazolam and reduced the time to extubation compared to midazolam and propofol. Compared to both propofol and midazolam, patients were more easily roused, more cooperative and better able to communicate whether or not they had pain. Dexmedetomidine treated patients had more frequent hypotension and bradycardia but less tachycardia than those receiving midazolam and more frequent tachycardia but similar hypotension to propofol-treated patients.
Pharmacokinetics: Distribution: Following IV administration, Icunes exhibits the following pharmacokinetic parameters: A rapid distribution phase with a distribution half-life (t½) of approximately 6 min; a terminal elimination t½ of approximately 2 hrs; and steady-state volume of distribution (Vss) approximately 118 L. Clearance is estimated to be approximately 39 L/hr. The mean body weight associated with this clearance estimate was 72 kg. Icunes exhibits linear kinetics in the dosage range of 0.2 - 0.7 mcg/kg/hr when administered by IV infusion for up to 24 hrs and it does not accumulate in treatments lasting up to 14 days. Dexmedetomidine is 94% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 0.85 to 85 ng/ml. Dexmedetomidine binds to both human serum albumin and Alpha-1-acid glycoprotein with serum albumin as the major binding protein of dexmedetomidine in plasma.
Biotransformation and Elimination: Dexmedetomidine is eliminated by extensive metabolism in the liver. There are three types of initial metabolic reactions; direct N-glucuronidation, direct N-methylation and cytochrome P450 catalysed oxidation. The most abundant circulating dexmedetomidine metabolites are two isomeric N-glucuronides. Metabolite H-1, N-methyl 3-hydroxymethyl dexmedetomidine O-glucuronide, is also a major circulating product of dexmedetomidine biotransformation. Cytochrome P-450 catalyses the formation of two minor circulating metabolites, 3-hydroxymethyl dexmedetomidine produced by hydroxylation at the 3-methyl group of dexmedetomidine and H-3 produced by oxidation in the imidazole ring. Available data suggest that the formation of the oxidised metabolites is mediated by several CYP forms (CYP2A6, CYP1A2, CYP2E1, CYP2D6 and CYP2C19). These metabolites have negligible pharmacological activity.
Following IV administration of radiolabelled dexmedetomidine, an average 95% of the radioactivity was recovered in the urine and 4% in the faeces after nine days. The major urinary metabolites are the two isomeric N-glucuronides, which together accounted for approximately 34% of the dose and N-methyl 3-hydroxymethyl dexmedetomidine O-glucuronide that accounted for 14.51% of the dose. The minor metabolites dexmedetomidine carboxylic acid, 3-hydroxymethyl dexmedetomidine and its O-glucuronide individually comprised 1.11 to 7.66% of the dose. Less than 1% of unchanged parent drug was recovered in the urine. Approximately 28% of the urinary metabolites are unidentified minor metabolites.
Special Populations: No major pharmacokinetic differences have been observed based on gender or age. Dexmedetomidine plasma protein binding is decreased in patients with hepatic impairment. Patients with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C) had decreased hepatic clearance of dexmedetomidine and prolonged plasma elimination t1/2. Although dexmedetomidine is administered to effect, it may be necessary to consider initial/maintenance dose reduction in patients with hepatic impairment depending on the degree of impairment and the response.
Icunes pharmacokinetics were not significantly different in patients with severe renal impairment [creatinine clearance (CrCl) <30 mL/min].
The pharmacokinetic profile of Icunes has not been studied in paediatric patients.
